Penile Prosthesis For ED

Dr. Jean-Francois Eid, of New York City’s Advanced Urological Care, is a urologist who specializes in treating advanced erectile dysfunction.

Prostatepedia spoke with him recently about penile prostheses after prostate cancer.

How did you became involved in treating men with erectile dysfunction (ED)?

Dr. Jean-Francois Eid: When I was a third-year medical student, I did a general surgery rotation in urology, and I went to a lecture about penile implants. I was fascinated that such a device could be made. Because I have an engineering background (I’m a material science engineer), I felt then it would be a dream to work with the industry that produces these magnificent devices, to continue to improve them, and invent surgical equipment to facilitate implantation. My dream came true.

I work with Boston Scientific and Coloplast, companies that make penile implant devices for men who suffer from ED. I’m on their advisory committee, and we collaborate in order to improve these devices. I have a few patents to my name as well. It’s been a great ride for the last thirty years.

I, of course, learned from a lot of many great implant surgeons and have benefited from their experience. I also felt that it was time for me to give back and I was very honored when I was asked to write a chapter on penile implants in the Campbell- Walsh urology textbook, required reading for all Urology Residents.

How common is ED after prostate cancer?

Dr. Eid: It varies depending on the treatment that the patient received and the level of erectile function the patient had before treatment. For example, if a patient had normal erections before radical prostatectomy, studies show that about 7 to 10% of these patients will have normal unassisted erections after the prostate operation. About 30% of these gentlemen will respond to oral therapy such as sildenafil or tadalafil. The remaining 60% will need a more advanced ED treatment option, such as a penile self-injection or a penile implant.

Patients who undergo radiation therapy fair a little bit better. They develop ED about a year to a year and a half after the radiation, and about 50% of these patients will respond to oral medications. The remaining will also need more advanced treatment options such as penile self-injection or penile implant.

What is the progression? You try medication first, and if that doesn’t work, then you go to injections, and finally something like a prosthesis?

Dr. Eid: Exactly. Patients who undergo radical or robotic prostatectomy tend to be younger and healthier, and we recommend a period of penile rehabilitation with either oral therapy, vacuum device or penile self-injections. The data supporting penile rehabilitation is not very robust, nevertheless if a patient had normal unassisted erections prior to the cancer treatment, I would recommend a 12 to 18 month waiting period before proceeding with a penile implant. He is unlikely to recover spontaneous erections beyond the 2-year period, however. Conversely, if a patient relied on oral medications or penile self-injection for satisfactory sexual intercourse prior to the prostatectomy, it is then very unlikely for erectile function to return. In that case, one may proceed with a penile implant before the 12 month waiting period. Oral medications and a trial of penile self-injection is always recommended before proceeding with a penile implant.

If a man struggled with ED before going into prostate cancer treatment, will that impact if he has ED after treatment?

Dr. Eid: Yes, the ED is more likely to be advanced and be more difficult to treat. Penile atrophy, deformity and permanent shrinkage are more likely to occur. Early placement of a penile implant may in that circumstance be a better option as it will prevent further penile deformity and shrinkage while restoring erectile function.

What is penile implant prosthesis, and what are the different types?

Dr. Eid: There are basically two types of penile implants: malleable and inflatable implants. Malleable implants are always firm and positional so that they can be concealed by manually bending it down when not in use. These are the simplest of the penile implant devices. However, the feel of the penis is not as natural as for the inflatable devices. Because the shaft of the penis is always firm, pressure atrophy of the flesh of the penis will occur over the long run.

The inflatable devices can be further divided into two groups: devices with a self-contained reservoir, also referred to as a two-piece implant and the multi-component implant with cylinders, pump, and a separate reservoir referred to as the three piece implant. The reservoir is needed in order to store the saline when an erection is not desired. The two-piece devices are comprised of a pair of penile cylinders with a small saline reservoir built into the back of each cylinder and a scrotal pump. To obtain an erection the scrotal pump is squeezed, transferring the saline from the reservoir into the cylinders. The volume of saline is limited, which means there’s a compromise between penile rigidity when inflated, and the flaccidity of the penis when the cylinders are deflated.

The three-piece inflatable implants are the more physiological devices with a better erection when inflated and better flaccidity when deflated. The separate reservoir is easily concealed and because it contains a much larger volume of saline it enables the bearer to have a much firmer erection.

There are approximately 25,000 implants performed in the United States every year of which 90% are the multi-component inflatable devices. These devices were invented in 1973, and they’ve been refined since. There are only two companies that make them: American Medical Systems, (Boston Scientific), and Coloplast. Both are excellent companies and current implants have an average life expectancy of 8 to 12 years. When they fail, they are easily replaceable. The procedure to remove and replace it is a lot less cumbersome for the patient because the space inside the penis is already fashioned. There’s less pain and swelling than for the original implant placement.

Is there a difference in performance between the two types of devices?

Dr. Eid: The multi-component inflatable devices give the most natural feel of the erection and are a lot more comfortable when the patient no longer wants to have an erection. The malleable implants have a very firm and abnormal feel to them. Over time, the flesh of the penis will become looser over the rigid cylinders. This renders the malleable implant to be less firm than the inflatable device. On the other hand, when the inflatable devices are deflated the cylinders no longer apply pressure on surrounding penile flesh, preventing long-term penile atrophy

When is a penile implant prosthesis a possible solution for men with ED? When is it not a viable solution?

Dr. Eid: Any man that can have an erection on his own or respond well to oral medications may forgo the need for a penile implant

We don’t expect patients who rely on penile self-injections to stay on them for the rest of their lives, and even if the response to injections is very good, it is not unreasonable to proceed to a penile implant. There are very few circumstances that contraindicate placement of a penile implant; these are the presence of an infection or in situations where the patient is medically unstable.

What is the procedure once he decides this is what he wants to do?

Dr. Eid: It is most important to seek the most experienced surgeon that one can find. That surgeon may not be necessarily the one closest to one’s home or in one’s insurance plan. A penile implant specialist is preferable to a general urologist. A penile implant specialist has a much greater success with fewer complications. Each specialist will have their individual pre-operative protocol.

Not a member? Join us to read the rest of Dr. Eid’s conversation about the penile prosthesis.

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How You Can Participate in Genomic Research

Dr. Eliezer Van Allen, Assistant Professor of Medicine at Harvard Medical School, a clinician at Dana-Farber/Partners Cancer Care, and an Associate Member at the Broad Institute of MIT and Harvard, focuses on computational cancer genomics, using new technology in precision medicine, and resistance to targeted prostate cancer therapies.

Prostatepedia spoke with him about how even those of you in remote areas can participate in nationwide genomic research study for men with advanced or metastatic prostate cancer.

What is it about medicine and caring for patients that keeps you interested and engaged?

Dr. Eliezer Van Allen: There are two answers to that question. One, the scientific answer, is that it’s been so remarkable to see how quickly advances that we’ve learned from studying patients with cancer have immediately translated into the clinic and have impacted my patients’ lives. It’s impacted people I don’t know, and that cycle of innovation is becoming quicker. It’s so exciting. It’s a privilege to be part of that from a professional level.

The other answer is more of a humanistic thing. I went into medicine because of my experiences at Camp Kesem, which is a camp for kids whose parents had cancer. It was a life-changing experience to be involved with that and to help drive it from the beginning. Whether or not any individual therapy works for any of my advanced cancer patients, there’s a human element to this job that’s very profound. That is also a privilege, to be involved with that day-to-day, no matter what.

Camp Kesem is still around, right?

Dr. Van Allen: Yes, it’s growing amazingly. There are over 100 camps now around the country, and thousands of families are involved. It’s wonderful.

Have you had any patients who changed either how you view the art of medicine or your own role?

Dr. Van Allen: Absolutely. At some level, every single patient both challenges and reinforces aspects of what it means to be a doctor and deliver care. Each in their own way has changed the way I think about things. There are obviously some stories that stand out and some experiences.

Some of the patients who’ve had the most catastrophic outcomes and succumbed to the disease in rapid form have taught me the most about what it means to live your life to the fullest, whatever that means to you. I have a lot of respect for them.

It’s a special thing to care for people at the particular moment, when they face big life questions.

Dr. Van Allen: About eight or nine years ago, I wrote a piece for the Journal of Clinical Oncology’s Art of Oncology series. It was about this one patient I had as a first-year fellow who had this positive thinking attitude in the wake of the most potentially catastrophic scenarios up until he passed away. It was such a surreal thing. In that case, it was rare, but I think it teaches you a lot about what it means to be human and how hard this disease is.

What is the goal of the Metastatic Prostate Cancer Project?

Dr. Van Allen: The Metastatic Prostate Cancer Project is a patient-driven research project whereby, rather than expecting the patients to come to us to join and participate in advanced research, we bring the project to their doorstep, and we engage with patients in new ways. We give patients an opportunity to share information about themselves and share their tumor specimens for us to do genetic testing. The goal is building the largest genomic registry of prostate cancer that we can learn from, and in so doing, accelerate that discovery to translation cycle even more.

Can you give us some updates on how the project has been going since you launched?

Dr. Van Allen: We launched this project in January 2018 in a patient population that is known not to talk about their disease in any venue, under any circumstances, to anyone. There’s no social media presence for this disease space, or at least on the surface, and frankly, we would’ve been thrilled had ten people signed up. Our sister project, the Metastatic Breast Cancer Project, has a loud and overt presence of women taking selfies with their saliva kits, so we weren’t sure how this was going to work.

We’re a little past a year from launch and over 700 men have engaged in research, given us consent to access their samples, filled out the patient-reported survey, and joined this Count Me In movement. It’s remarkable, but not only have these 700 men signed up, we’re already at the other end of the cycle of this project now, and we’ve generated complete data sets for the initial wave of these men. By complete data set, I mean genetic, clinical, and patient-reported data, and we’ve put that data out to the entire community in the research setting to learn from.

This proves the principle that we mean what we say when we’re generating data for the community. We’re not trying to build a silo here. This is patient-demanded, and therefore patient-driven, from day one. From every aspect across the board, it’s been remarkable and exciting to see how we’ve done so far.

We are 150% absolutely still looking for patients. We’ll always be looking for patients. Anyone who’s interested should feel comfortable to go to MPCProject.org and click Count Me In.

What kinds of patients should join? Anyone with prostate cancer?

Dr. Van Allen: This project is for advanced or metastatic prostate cancer, which means prostate cancer that’s left the gland. That could be folks with local, regional prostate cancer involved in the lymph nodes, folks with biochemical recurrence only (only PSA detected in the blood), and all the way to patients with heavily pretreated, advanced disease that’s spread to bone, liver, or wherever. Anyone in that spectrum is considered advanced or metastatic from our perspective.

The project is basically unending, right?

Dr. Van Allen: That’s the goal, releasing it as fast as we can.

Do you just release the data, or are you also forming collaborations with other institutions or projects?

Dr. Van Allen: We’ll release the data. We’re obviously going to try to learn from it ourselves and use it to come up with perhaps new drug targets, biomarkers, and whatnot, but also we would like to connect with other efforts that are spiritually aligned in any way that’s feasible.

One of the best outcomes would be that some researcher who is in no way affiliated with our project finds our data useful and uses it for their research to inform what they do. We’re already starting to see that happen with our sister projects where there are scientists and labs that we are not affiliated with who are using the data to inform how they think about their research and their projects. All of those outcomes are on the table, and we’re excited to pursue all of them.

Is there anything else you want patients to know about how the project is doing, about further studies you’re doing, or other studies you think people may find interesting?

Dr. Van Allen: This is a patient-driven project. Some of the patients who’ve given us feedback on their experiences so far have also prompted questions that we can ask that we, in our little academic bubble, probably would’ve never thought of. That’s how we’re starting to dive into things that are driven by patient experiences or that we’re observing in the patients who have signed up, down to questions that might seem curious but are illuminating, ones that we hadn’t intended initially.

For example, in the first patient data release, when asked if they had surgery for their prostate, almost half the patients marked: “unknown.” We can compare that to their medical record and sort that out, but it provides a window into something that wasn’t the initial intent of the project. That feedback opened up a lot of interesting questions and opportunities for research that we hadn’t necessarily anticipated up to that point.

Men didn’t know if they’d had prostate cancer surgery or not?

Dr. Van Allen: It may have been the way we asked the question. It may have been that patients were interpreting what they were supposed to answer. We don’t know. The point is that this is not something we initially set out to do, but it is an early example of how patients can guide where the research needs to go.

I just presented this project at the American Urologic Association meeting, and a gentleman came up to me afterwards. He’s had metastatic prostate cancer for four years and a complete response to cancer immunotherapy, and he wanted to know if he was eligible for this project. Not only is he eligible, but he’s an extraordinary case. We want to understand why. This patient is not within 500 miles of an academic medical center, and he would otherwise never be approachable or available to engage in research. We exchanged information, and he’s going to sign up.

Patients may not realize: they have the power to drive this field forward in this unique way. It’s not something that medicine is used to doing. We want to get the message out that this is all starting with patients and their ability to contribute. That will determine how far this goes.

It’s easy for them to participate: go to the website, fill out the forms, and give a blood sample?

Dr. Van Allen: Yes. You don’t even have to do the blood sample if you don’t want to. It’s exactly what you described. Go to the website, click a few buttons. There’s a very simple online consent form. We’ll send you a saliva kit and a blood biopsy kit and take it from there.

Can you still participate even if you’re in a remote area?

Dr. Van Allen: Yes, anywhere in the United States and Canada. For the blood biopsy, we send you a kit, and you bring it to your next lab draw, PSA test, or whatever, and there are instructions in the kit for the phlebotomist. In some cases, phlebotomists have not been willing or able to participate, so we can provide vouchers to patients to do it at a Quest Diagnostics lab or somewhere convenient to them. The intent here is that the patient bears no financial burden in participating.

Not a member? Join us.

Reporting Clinical Trial Results

Ms. Merith Basey is the Executive Director of Universities Allied For Essential Medicines (UAEM) North America, a global network of university students who believe that their universities have an opportunity and a responsibility to improve access to publicly funded medicine developed on their campuses.

Prostatepedia spoke to her about UAEM’s transparency campaign to get universities to report the results of the clinical trials they run and how prostate cancer patients can help.

Not a member? Join us.

How did you get involved with health advocacy?

Ms. Merith Basey: A little bit by accident. My interest in public health and health advocacy stemmed from my undergraduate degree in modern languages and my interest in Latin America.

In 2004, I volunteered with an organization in Ecuador called AYUDA in conjunction with a local diabetes foundation that worked with children with Type 1 diabetes and their families. We worked together to provide diabetes education to children with Type 1 and their families so that they could learn how to better manage their condition and increase access to resources.

It changed my life. I ended up working for that organization for a number of years in a number of different settings. However, during that time, I began to see that, in some of the countries in which we worked, access to insulin was an ongoing challenge, and for many families, the price of insulin was simply too high. The lack of action at that time spurred me and a small group of advocates to launch the 100 Campaign for access to insulin back in 2012. Today, one in two people who need access to insulin still don’t have regular access, a challenge that is increasingly apparent in the United States and in many countries around the world. It was through this lens that I ended up in health advocacy.

What is Universities Allied for Essential Medicine?

Ms. Basey: Universities Allied for Essential Medicine (UAEM) was founded in 2001 at the height of the HIV/AIDS epidemic. A drug called d4T, or stavudine, had been developed at Yale University with public funds and was being used as part of a cocktail of drugs, at least in the United States, to treat people living with HIV.

At the time, Doctors Without Borders/Medecins sans Frontiers (MSF) was looking to treat people living with HIV in South Africa where the burden of disease was highest. They realized that the price of this one drug was too high for them to be able to treat the millions who were in need of access to treatment. However, a young student and activist who started Yale law school that year decided to take action. She organized, with other students in conjunction with MSF and Civil Society, with the goal of lobbying her university and the company Bristol-Myers Squibb (who had purchased the rights to the drug) to change the license between them to allow for the legal generic importation of this drug into South Africa. The campaign was a success; it led to a 90 percent reduction in the price of that drug in that region, allowing MSF to treat people living with HIV for the first time.

That’s the founding story of UAEM and is at the heart of our work, primarily based on university campuses in the United States and today in over 20 countries around the globe. A simplified vision of our work is that we believe no one should be poor because they’re sick or sick because they’re poor.

We understand the role that universities have in the drug development pipeline and believe that they should be critical partners and leaders in ensuring access to affordable medicine, especially when it is developed with taxpayer funds. Also, in particular, we work to urge universities to increase their research into neglected diseases since most research in the current system tends to go into drugs or treatments for wealthier and historically whiter populations. A lot of other drugs for diseases that predominantly impact the poor are left behind until there’s an urgent demand like there was for Zika and Ebola. It is estimated that 90 percent of the research dollars go to just 10 percent of the global burden of disease.

Do you focus on universities because that is where some of this initial research is done or because you’re trying to activate younger students on campus?

Ms. Basey: I think it’s both in part. Initially, it was inspired by that success story at Yale, but it was also about understanding where students have power. Students are key stakeholders in university systems, and while they are actively enrolled, they have unique power and access to faculty and other decision-makers. They have the right to be able to meet with the administration, ask them about their policies, and urge them to address historic inequities or errors.

Secondly, universities are the key drivers of much of our most innovative biomedical research. In the United States, for example, every year $37 billion of taxpayer money goes in the form of grants from the National Institutes of Health (NIH) to universities across every state and in a number of countries around the world to do biomedical research and clinical trials.

Given this massive public investment into researching and developing new compounds and medical innovations, it is also an opportunity to influence the way that those drugs are patented and eventually licensed into the hands of pharmaceutical corporations down the line. We also believe that the public should have a return on that investment and that the product of that investment should be accessible and affordable to the people who paid for them in the first place: the public.

Yes, the National Cancer Institute (NCI) and the National Institute of Health (NIH) fund quite a number of clinical trials. Most of the people reading this are familiar with trials as potential participants. But what happens when a trial is completed?

Ms. Basey: It depends on who is leading the trial. In the United States, for example, when a university is responsible for leading a clinical trial and it is completed, the results should be reported onto a public database within a period of 12 months. (There are of course exceptions based on a number of different criteria). A significant portion of NIH funding is invested into clinical trials. It’s estimated that in 2017, at least about 38 percent of that $37 billion figure that goes to universities actually goes directly into funding for university-driven clinical trials, clinical research, and other activities related to clinical trials.

On average, however, it has been estimated that only about 50 percent of clinical trials are registered and reported. This obviously has impact. I can’t speak for the specific motivations that certain individuals might have for entering a trial, but in general, people participate to help find out more about the effects of specific treatments on a particular disease whether that be in the hope of helping improve their own health or the health of others. Knowing that, it’s unethical that this data goes unpublished.

Why is this data not reported?

Ms. Basey: A couple of things are happening. Obviously, that 50 percent is a global figure so it is a global problem. In the United States, however, even though the FDA Amendments Act makes it required by law for certain trials to be posted, according to UAEM’s recent report (www.altreroute.com/ clinialtrials) 31 percent of trials that are due are still missing results on the public registry with performance varying strongly between the top 40 institutions reviewed. Why are they not reporting? In some cases, they don’t report because they haven’t been required to, because it takes time, and because often the results are not favorable to the people funding the trials. Trials with negative results are two times as likely to go unreported as trials with more positive results. Publications typically like to report favorable outcomes rather than negative outcomes. If you are a private pharmaceutical corporation funding a trial for a drug you intend to produce and the initial results are not in your favor (due to limited effects on health outcomes or number of adverse effects) or if there isn’t a legal obligation to report, you may choose not to publish data. Obviously, this is entirely unethical but the evidence suggests it happens.

Best practices are set out to say that all clinical trials should be posted because, without all the data it’s going to skew data in a manner that is ultimately harmful. It’s going to skew the results. It’s going to skew the information that doctors are going to have in terms of deciding which drug is safer than another. The system is flawed in that sense. Failing to publish trial results means the decisions-makers with regards to medical treatments won’t have full information about the benefits or risks of treatments.

Just to clarify for patients, how are the results of clinical trials usually reported?

Ms. Basey: In the United States, a trial would first have to register on clinicaltrials.gov when the trial starts. (Although not all studies are required to be registered, e.g. observational studies or trials that do not study a drug, biologic, or device). Clinicaltrials.gov is a United States government database that has all that information for both federally and privately funded trials conducted under investigational new drug applications to test effectiveness of experimental drugs for serious or life-threatening diseases or conditions. Because of this FDAAA Final Rule, specific trials that involve patients will need to register or report their data within 12 months on that same database. At UAEM, in conjunction with TranspariMED, we just looked at the top 40 United States universities driving a lot of this biomedical innovation via clinical trials. Even though the law required that they register and report data within 12 months, about a third of these university-driven trials were unreported.

Essentially, they’re breaking the law. For every day that they hadn’t reported, the FDA could fine them $10,000. There’s quite a large incentive (beyond the ethical one) for them to report, but the FDA so far hasn’t collected any fees. We need to be making sure that all data and all trials are ultimately registered and reported so that there is full transparency and full information for everybody in terms of open data. It really comes down to making sure that data isn’t hidden.

So you’re running an awareness campaign?

Ms. Basey: For us, it’s very clear that, as receivers of public funds and given their social missions, universities should be leading the way in terms of registering and reporting of their own clinical trials. The campaign that we’re running is not only to urge universities to register and report but to go a step further. The World Health Organization (WHO) developed a joint statement on public disclosure of results from clinical trials. This was first signed in May 2017 by 21 key funders of clinical trials around the world including the Wellcome Trust, the Gates Foundation, MSF, the Indian Council of Medical Research and the Drugs for Neglected Diseases Initiative, just to name a few. They agreed, that if they fund clinical trials they will require investigators to register and publicly report the results in a timely manner. We go little bit further because we are also asking those universities or institutions to come up with a policy to hold themselves and others accountable. We have students in over 50 universities in North America and in 20 different countries around the world organizing on their campuses to urge their universities to make sure that they’re registering and reporting their own clinical trials and thinking about signing this WHO joint statement on clinical trial transparency.

Is there anything that my readers can do to help?

Ms. Basey: If you’ve had the privilege of going to a university, call or email your alma mater to ask them about their policy or their performance if they are listed in our report. Let them know that this is something you support and you’d like them to take action. We know that universities respond to pressure from their alumni. You could also financially support UAEM’s grassroots campaign directly via http://www.UAEM.org

At UAEM we will continue to urge universities to step up to their commitments. They are, ultimately, morally bound to be transparent with their research outcomes since most of these trials are publically funded. We’re really proud to see that the universities that are 100 percent reporting are actually beginning to mobilize and think about moving forward with signing onto the WHO statement. But we still have a long way to go. Every pressure and encouragement is recommended.

Clinical trial transparency helps accelerate medical progress for new treatments and improve our understanding of treatment efficiency and safety, ultimately contributing to improved access to medicines and better health outcomes for us all.

Not a member? Join us.

February: Heart Health + Prostate Cancer

In February, Prostatepedia is talking about cardiovascular risk in prostate cancer patients. Dr. Charles Snuffy Myers frames the discussions for us.

“It turns out that the relationship is complex. Men with cardiovascular disease have a higher incidence of prostate cancer. This may, in part, be due to an impact of elevated cholesterol on prostate cancer progression. However, other factors may also be involved. For example, obesity is associated with an increased risk of cardiovascular disease and with progression of prostate cancer. Similarly, a diet rich in calories and meat is associated with an increase in insulin like growth factor 1 and this hormone has been linked to prostate cancer progression.

Removal of androgens, such as testosterone and dihydrotestosterone, plays a central role in the treatment of prostate cancer. In turn, low testosterone exacerbates insulin resistance, diabetes, visceral obesity and hypertension—known risk factors for cardiovascular disease.

In this issue, Dr. Pedro Barata from Tulane University gives us an overview of the issues at stake when we discuss prostate cancer and cardiovascular disease.

Dr. Michael Freeman from Cedars- Sinai discusses the evidence that cholesterol might drive progression in prostate cancer and the possibility that lowering cholesterol with statins might have a therapeutic impact. One of the more interesting observations he discusses is that certain gene expression patterns might lead to a increase or decrease in sensitivity to cholesterol levels.

Dr. Matthew Roe, a well known cardiologist from Duke University’s Clinical Research Institute (DCRI), speaks about the PRONOUNCE clinical trial he’s running. PRONOUNCE compares the cardiovascular safety of Firmagon (degarelix) versus Lupron (leuprolide) in men with advanced prostate cancer.

Dr. Darryl Leong from Canada’s McMaster University talks about his RADICAL-PC clinical trial, which evaluates the effectiveness of modifying cardiovascular and lifestyle risk factors in men who’ve just been diagnosed with prostate cancer.

Finally, Dr. Christina M. Dieli- Conwright talks about her clinical trial evaluating a 16-week program of cardiovascular and strength exercises in men with prostate cancer.”

Join us to read our February conversations about heart health + prostate cancer.

Combining Keytruda (pembrolizumab) and Xtandi (enzalutamide) For Prostate Cancer

Dr. Julie Graff is a medical oncologist at Oregon Health & Sciences University.

Prostatepedia spoke with her recently about her continuing work on combining Keytruda (pembrolizumab) with Xtandi (enzalutamide).

What are Keytruda (pembrolizumab) and Xtandi (enzalutamide)? How and when are they used in prostate cancer patients?

Dr. Graff: Keytruda (pembrolizumab) is an intravenous antibody to PD-1 or programmed death 1 on immune cells, in particular T cells. When that protein is present, it can interact with tumor cells that have PD-L1 and through that interaction the tumor cells turn off the immune system. We consider it a checkpoint inhibitor.

We’ve known for a long time that in some cancers T cells, which are the part of the immune system that can kill cancer cells, are present in the tumor and yet they’re not actually killing the tumor. Over the decades we’ve learned that some of those cells, not necessarily T cells but immune cells in the environment, are actually helping the tumor grow. We’ve also learned that some of them are trying to fight the tumor, but they’re being turned off by the tumor.

Keytruda (pembrolizumab) can block that negative signaling, thereby activating the immune system. It was first approved in melanoma and has received multiple subsequent approvals. So far we don’t have great markers for knowing who will benefit from the drug and who won’t, but we are working on that.

Xtandi (enzalutamide) is a drug that binds to the androgen receptor, which is inside the prostate cancer cells, and prevents it from interacting with androgens or male hormones. In that fashion, it leads to some cell death and helps people live longer. It’s been FDA approved since 2012 in the post-chemo setting, and now it has been approved in the pre-chemotherapy setting. It used to be approved only in metastatic disease, and now it’s approved in non-metastatic castrate-resistant disease. It’s being applied in different stages of the disease.

What is the rationale behind combining these two agents?

Dr. Graff: In studies where checkpoint inhibitors like Keytruda (pembrolizumab) are used alone, there’s not a lot of tumor activity. There’s certainly not a good rationale to use Keytruda (pembrolizumab) by itself in prostate cancer. Maybe as time goes on we’ll find that perhaps 2 out of 100 patients have certain mutations that make the Keytruda (pembrolizumab) alone helpful, but we’re not yet there.

There wasn’t a great reason to use Keytruda (pembrolizumab) by itself, so we began to think about combinations. Xtandi (enzalutamide) was felt to upregulate PD-L1 on dendritic cells, in particular when people became resistant to the Xtandi (enzalutamide), so that was one initial reason.

Castration therapy may reinvigorate the immune system. When you’re maturing as a child, you have a thymus gland behind your sternum that helps create new T cells. As you go through puberty, that gland shrinks and becomes inactive, so you don’t make new T cells.

It looks like maybe the thymus increases again during castration therapy; there’s a hypothesis that you’re creating new T cells.

There is also a reason to think about Xtandi (enzalutamide) in particular. It’s helping in those two regards.

Also, if you used Keytruda (pembrolizumab) in combination with chemotherapy, you would be at risk of killing a lot of immune cells with the chemo itself. If you used Keytruda (pembrolizumab) in combination with Zytiga (abiraterone), which is like Xtandi (enzalutamide), you would have to use prednisone, which would perhaps dampen the immune response. When our study was designed in 2014, it made a lot of sense to combine Keytruda (pembrolizumab) with the Xtandi (enzalutamide).

What have studies revealed about the combination? Is it effective? What kind of side effects do patients experience?

Dr. Graff: We did a Phase II study looking at 28 patients with metastatic castrate-resistant prostate cancer whose cancers were progressing on Xtandi (enzalutamide). We added 4 doses of Keytruda (pembrolizumab). We saw 5 responded in that group of 28. That’s only 18%, but when they responded, they responded spectacularly.

The most extreme case was a gentleman who started out with a PSA of 2,500 that went down to 0. He had big, bulky liver tumors that just shrank away. He must be two and a half, almost three years out from treatment and he’s still in complete response. His case is extreme. But when we do see responses, they’re spectacular.

If those five patients had only had a dip in their PSA or something less impressive, the study wouldn’t be as important as it was. Then we had four other people who had very durable responses as well. That’s the benefit part of the study.

But there are known side effects with each of these drugs. With Keytruda (pembrolizumab), when you stimulate the immune system you run the risk of the immune cells killing or attacking healthy tissue. For example, a patient on Keytruda (pembrolizumab) could develop autoimmune hepatitis where the immune cells are attacking a healthy liver. There are some bad sides to stimulating the immune system.

In our study, we did see some of those side effects. In these 28 patients who were treated, we did have patients who had autoimmune toxicities in which their own immune cells attacked healthy tissue. We had four patients who had thyroid dysfunction, which is a fairly well recognized side effect of Keytruda (pembrolizumab) that is easy to manage with thyroid medicine. We had a couple people with colitis, which happens when the immune system attacks the colon; that has to be managed with high-dose steroids and sometimes biologic drugs that GI specialists use. We saw side effects that we would expect from Keytruda (pembrolizumab) and we saw some side effects that we would expect from Xtandi (enzalutamide) such as fatigue. Since these patients had already been on Xtandi (enzalutamide) for a long time, we did not observe worsening of the Xtandi (enzalutamide) side effects with the addition of Keytruda (pembrolizumab). We mostly just saw those Keytruda (pembrolizumab) side effects.

Any follow-up studies planned?

Dr. Graff: We got funding from Merck to add another 30 patients on to that study. Those 30 have already been enrolled and treated. For those patients, we insisted on a biopsy. For the first 28 patients, we asked them to get a biopsy if they had a tumor that could easily and safely be biopsied. In the next 30 patients, we required that they have a biopsy. We have now a nice array of tissue from these 58 patients and we’re working on getting the results. We have some multiplex stains and hope that the paper can come out next year.

Join us to read about another of Dr. Graff’s clinical trials that will be accepting patients shortly.

Immunotherapy For Prostate Cancer

In January, we’re talking about immunotherapy for prostate cancer. Dr. Charles Myers introduced the issue for us.

Not a member? Join us to read this month’s conversations about immunotherapy.

The goal of this issue is to capture the current state of the art in immunotherapy of prostate cancer. We live in a time when immunotherapy is making major contributions to the treatment of many malignancies. The Nobel Prize was recently awarded for the discovery of checkpoint inhibitors that have revolutionized the treatment of melanoma. Chimeric antigen receptor T (CAR T) cell therapy represents a major advance in the treatment of B-cell lymphoma.

Unfortunately, immunotherapy has not yet had such a dramatic impact on prostate cancer treatment. The Provenge (sipuleucel-T) vaccine has been approved for prostate cancer treatment because it results in a modest improvement in the survival of patients with advanced disease. The checkpoint inhibitors have not shown useful activity in prostate cancer, although a small group of patients have had dramatic responses. The current situation may be best summarized by saying that immune response to prostate cancer can be demonstrated in patients, but various factors appear to limit cancer cell kill.

In this issue, we feature conversations with investigators who are doing interesting research on how to overcome factors limiting the effectiveness of immunotherapy in prostate cancer.

Dr. Charles G Drake talks about the state of immunotherapy in 2018 and looks ahead to what we can expect to happen in 2019.

Dr. James Gulley talks about why the initial trials with the prostate cancer vaccine ProstVac didn’t prove as promising as we’d all hoped. He also outlines a number of prostate cancer vaccine clinical trials looking for patients.

Dr. Julie Graff discusses clinical trials—both completed and those looking for patients—that combine Keytruda and Xtandi.

Dr. Fatima Karzai tells us about clinical trials at the National Institute of Health that combine PARP and PD-L1 Inhibitors.

Dr. Bruce Brown, Chief Medical Officer of Dendreon, discusses a clinical trial that looks at using sipuleucel-T in men on active surveillance.

Each conversation this month includes information on clinical trials that are recruiting prostate cancer patients. If you think you may be a fit, please don’t hesitate to contact the investigator.

Join us for more information.

Dr. Mohit Khera: Treating ED

Dr. Khera, a urologist specializing in male infertility, male and female sexual dysfunction, and declining testosterone levels in aging men, is the Director of the Laboratory for Andrology Research and the Medical Director of the Executive Health Program at Baylor College of Medicine in Houston, Texas.

Prostatepedia spoke with him recently about current and emerging approaches to erectile dysfunction (ED) after prostate cancer.

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Why did you become a doctor?

Dr. Mohit Khera: Originally, I was a healthcare analyst. I did my MBA and then worked as an analyst in Boston for two years. I realized that it wasn’t very satisfying for me. I really wanted to be able to help other people and to help patients. I went to medical school and became a doctor. I have never looked back. It’s the best decision I ever made.

There’s something very gratifying about being able to help other people, particularly those who are in need and are in pain or hurting.

Have there been any particular patients who’ve changed how you see your role as a doctor or how you view the art of medicine?

Dr. Khera: There are numerous patients who stand out in my mind, particularly those who have suffered from prostate cancer and are trying to recover their lives, whether it be in terms of sexual function, incontinence, or even just keeping the cancer from coming back. It’s very challenging. These patients just

who is not very skilled or who does not do robotic prostatectomy quite frequently, their ED rates tend to be higher than someone who does the procedure on a regular basis. Surgeon skill is critical.

Typically, radiation does have a lower rate of ED initially, but several years down the road, the rate of ED can catch up and accelerates past the rate of ED from surgery.

We know that in androgen deprivation therapy (ADT) when you drop testosterone values, the risk for ED is significantly increased. Many studies show that you start losing nocturnal erections when the testosterone levels fall below 200. That’s exactly what happens when you give men ADT: ED rates should go up significantly.

Does erectile function come back after a man goes off ADT?

Mr. Khera: Yes, many times it does come back. The only problem is that not all men have their testosterone levels bounce back into the normal range after they stop ADT. Some men will actually have testosterone levels that remain in the low range. Of those men in whom levels do go up, whether they build up naturally or through testosterone supplementation, many will experience improvements in their erectile function once again.

Is there anything a man can do before treatment to prevent problems or reduce problems after treatment?

Dr. Khera: The concept of penile rehabilitation has been up for debate in my field. There are those who are proponents and those who don’t believe that it will help. I personally believe that penile rehabilitation is effective and will help patients recover their erectile function faster and more effectively.

In my program at Baylor College of Medicine, I start patients two weeks prior to the surgery on daily Cialis (tadalafil). I teach them how to use the vacuum erection device as well because I want them to use it after surgery. I check their testosterone levels before surgery, as some studies have shown that the testosterone levels do go up after a prostatectomy.

I also teach them the concept of penile injections just in case they need to use them after surgery if they’re not able to recover their erectile function.

There is a lot of counseling that goes on before the surgery. I put them on certain medications. I’m trying to prepare them for the surgery and to keep their tissue healthy and in the best condition possible.

There are a lot of doctors, though, who don’t do that kind of thing and who don’t talk about penile rehabilitation. Some aren’t even comfortable talking about ED with their patients except in the most cursory way. What would you say to a patient who’s encountered that? Should he go see someone who is a specialist in ED?

Dr. Khera: I think that patients should voice their opinions. If you look at this field 20 years ago, you realize there are three things that occur. A man wants to make sure that he gets his cancer out; he wants to make sure he can still get good erections; he wants to make sure that he’s not leaking urine after the procedure. Those are the three big categories of patient concerns.

In the past, many surgeons just focused on getting the cancer out and felt patients should be grateful for that. Yes, you may have some ED or incontinence, but we saved your life.

But now patients are very savvy and are demanding more. They’re demanding that they should have their cancer out and also have great erections and no incontinence after the procedure.

I think it’s very important when a patient has a diagnosis of prostate cancer that he discuss all three of these categories with his surgeon. They should discuss outcomes and the surgeon’s skill. They should discuss how many cases that surgeon has performed in this field.

Some patients in smaller communities don’t have access to doctors with your experience. Are there online resources for men in that position?

Dr. Khera: I think one of the best online resources is at http://www.sexhealthmatters.org. They have a phenomenal website with lots of literature and education on sexual medicine and rehabilitation. It’s an excellent resource that I share with my patients.

What about men who have already been through treatment and are suffering from ED? Which approaches seem to be most effective after which prostate cancer treatments?

Dr. Khera: There are many treatment options available to men with ED following a radical prostatectomy. The most common treatment options are PDE5 inhibitors. Those are called phosphodiesterase inhibitors—Viagra (sildenafil), Levitra (vardenafil), Cialis (tadalafil), and Stendra (avanafil).

These medications are very useful. Many of us give these medications on a daily basis to help men recover the nerves and penile tissue. I think it’s important.

Men can also use a vacuum erection device, which is exactly what it sounds like. It’s a vacuum that induces an erection. A band is placed at the base of the penis to maintain the erection.

Men can also use an injection therapy. We spend an hour in the office teaching them how to inject themselves with a very small diabetic needle. They inject into the base of the penis a solution that causes a very rigid erection. Then very early on they can start engaging in sexual activity.

I believe psychologically it’s very important that men start engaging in sexual activity early after surgery; it has a large psychological impact not only on the patient but also on the partner.

Other therapies include urethral suppositories called MUSE (alprostadil). These are placed into the urethra and dilate the penile tissue to give an erection.

Finally, I would say one of the best treatment options for many men is a penile prosthesis. We do perform this procedure. We place a penile implant into the penile tissue and a pump into the scrotum. Men can then pump saline into their penile tissue to induce an erection.

Isn’t it dangerous for a man to begin sexual activity soon after surgery? Is there any risk to him?

Dr. Khera: Typically in our practice, we like men to wait at least one month so that all the sutures heal and there is no risk of injury with the urethral anastomosis. We encourage men to start engaging in sexual activity one month after surgery.

Do you have any advice for men who are either worried about ED before going into treatment or who are struggling now?

Dr. Khera: There are two important things men should realize. First, prior to going into any type of treatment for prostate cancer, you should discuss ED outcomes with your doctor. Ask them what success have they had with ED. What is their plan for managing the ED if it does develop after the procedure?

Second, men who are already suffering from ED should know that there are excellent treatment options available. Men do not have to live with ED following a radical prostatectomy.

There are new treatment options emerging. We have started two studies, one with stem cell therapy. We take stem cells from men and inject them back into the penile tissue, with some benefit. We have another therapy called low-intensity shock wave therapy, in which we deliver shocks to the penile tissue. It does help recover erectile function.

There are many new treatment options on the horizon.

We’ve spoken about stem cell therapy before. I think you were just starting a trial.

Dr. Khera: I finished that trial and am now starting a Phase II trial. This first trial went extremely well. We’ll begin recruiting patients at the end of this year.

What we did not discuss last time was shock wave therapy. That has been out for multiple years and has gained a lot of success and media in the United States. Some of your readers may have seen commercials for it. We believe at this point that shock wave therapy should be used only in a research protocol until more data is available.

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Dr. Charles Drake On A Memorable Patient

Dr. Charles G. Drake is the Director of Genitourinary Oncology, Co-Director of the Cancer Immunotherapy Program, and Associate Director for Clinical Research at the Herbert Irving Comprehensive Cancer Center, New York-Presbyterian/Columbia University Medical Center.

Dr. Drake discusses a patient whose case intrigued him.

Have you had a particular patient who changed how you approach your work?

Dr. Charles Drake: Absolutely. I had a gentleman who had metastatic, castrate-resistant prostate cancer. He had been treated with hormonal therapy. He was about to go on chemotherapy. He had progression in his bone lesions, but he developed hematuria.

On CT scan, there was a fairly clear lesion in his bladder. We couldn’t tell what it was just by the scans, and his PSA was doubling quickly, it had reached 30 or so in less than a couple of months. We sent him to Dr. Ronald Rodriguez, who was at Johns Hopkins at the time, and he thought it looked like this was probably metastatic prostate cancer invading the gentleman’s bladder. Dr. Rodriguez did a transurethral fulguration, meaning he burned all of the tumor he could find in the bladder. After the procedure, he told me that there was a fair amount of prostate cancer left behind. While the procedure went well, and he got most of the tumor, he didn’t get all of it.

What happened next was fascinating. The patient’s PSA dropped. His PSA went from 30 to 20 to 10. It eventually nadired, or reached its lowest point, at less than 1 ng/ ml and he remained in remission for nearly two years. Although clearly anecdotal, in my mind, there is almost no question that this was one of those anecdotal abscopal responses, which makes you believe that it can happen. Almost certainly that was what happened for this patient. I’ll never forget it, frankly.

Interesting. An unexpected systemic response from local treatment, right?

Dr. Drake: Yes. It was brilliant. Just by treating the local disease in the bladder, this gentleman did well for over two years before it apparently progressed again, and he wound up getting chemotherapy. He also did very well with the chemo, so in my hopeful view, that suggests that maybe this fulguration procedure sparked a systemic immune response.

Join us to read the rest of Dr. Drake’s comments on the elusive abscopal effect.

Dr. Robert Bristow On Precision Radiation Therapy

Dr. Robert G. Bristow is the Director of the Manchester Cancer Research Centre (MCRC) at the University of Manchester in the United Kingdom.

Prostatepedia spoke with him about precision radiation therapy.

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What is meant by precision radiotherapy?

Dr. Robert Bristow: There are at least two aspects to precision radiotherapy. The first is the “physical precision” of radiotherapy; the actual targeting of the radiation beams or radioactive compounds to the specific tumor tissues that you want to treat, with maximum protection to the normal tissues that surround that particular tumor. For example, external precision radiotherapy uses intensity modulated radiotherapy or proton therapy where you then deliver the radiation in very precise defined volumes.

The other type of physical precision in radiotherapy uses brachytherapy, actually placing seeds or catheters with radioactivity directly in the prostate and being able to conform the dose tightly to the prostate gland, with that dose falling off rapidly around the surrounding normal tissues that could acquire side effects (e.g. the bladder or rectum). The concept of physical precision has allowed us to increase the total dose to the prostate cancer and yet maximally spare the normal tissues from side effects.

Another aspect of precision radiotherapy is “biological precision” whereby we think about the entire treatment using radiotherapy based on the innate characteristics of a particular patient’s tumor.

This includes information about the genetics and microenvironment of the tumor cells within the cancer that make it uniquely suited to be cured by radiotherapy alone, or in combination with drugs that modify biology or the immune system.

This can have the effect of increasing the chance that the cancer is cured locally and also attack cancer throughout the entire body to kill what we call occult, or hidden, metastases.

Precision radiation therapy therefore now means both an understanding of the biology of the tumor in a specific patient as well as physics to optimally deliver that radiotherapy.

What role does functional imaging play?

Dr. Bristow: Imaging is a cornerstone for staging cancer and understanding its biology. It is absolutely required for staging patients to understand the anatomy of their cancer—not only where the local tumor is, but also the spread to the pelvic lymph nodes and beyond that to the bone, for example.

Anatomic imaging therefore gives us the geography of where those tumors are in the body. Functional imaging adds further components to start to understand the biology of those tumors. For example, by using functional imaging with MRI, we can look at differences in tumor blood flow, oxygen levels, or metabolically active versus metabolically inactive tumors.

For PET scanning, we can use specific radioactive tracers that will tell us about the glucose in the tumor, the amount of the tumor that has low oxygen status (called hypoxia), and the relative growth rate of tumors.

So imaging can now give us both anatomy and biology.

Totally different world, right?

Dr. Bristow: It is. If you understand the biology from the imaging and where things are, you can certainly target specifically those areas with precision radiotherapy using novel biological agents, which we call molecular targeted agents.

Join us to read the rest of Dr. Robert Bristow’s comments on radiation therapy for prostate cancer.

Prostatepedia’s July Issue On RT

When you’re diagnosed with prostate cancer, you’re usually offered three options: monitor the cancer to see if it progresses, elect to have your prostate surgically removed, or elect to have the cancer treated with radiation therapy. Radiation is also used after surgery or in the event that the cancer comes back after that initial treatment.

Most of you are familiar with radiation therapy for prostate cancer—how it works, potential side effects, and special considerations. Even if you have not had radiation, chances are you’ve got a friend of relative who has.

This month, however, we’re delving into less often discussed aspects of radiation therapy: the role genomics will play in radiation therapy, why we might consider combining radiation with immunotherapy, the impact imaging has on radiation therapy, and the role radiopharmaceuticals play.

Dr. Robert Bristow of the University of Manchester gives us a sweeping overview of precision radiation therapy—from functional imaging to genomics—as well as a run-down of molecularly-targeted agents.

Dr. Charles Drake of the New York- Presbyterian/Columbia University Medical Center discusses radiation therapy and the elusive but intriguing abscopal effect.

Dr. William Hall of the Medical College of Wisconsin talks to us about the precision radiotherapy movement and how it will revolutionize patient care.

Dr. Daniel Spratt of the University of Michigan Health System talks about a clinical trial he’s working on with

Dr. Felix Feng from the University of California, San Francisco (UCSF) that uses genomics to determine which patients will receive a combination of radiation therapy and Erleada (apalutamide) and which will get a placebo.

From Dr. Ralph Weischelbaum of the University of Chicago we hear about the thinking behind combining radiation therapy with immunotherapeutic agents—with a cautionary note.

Dr. Johannes Czernin from the University of California, Los Angeles (UCLA) talks about a clinical trial he’s running on a radiopharmaceutical agent—a PSMA targeted lutetium-177. He is looking for patients to join, so if you think you might be a fit, please reach out to him at the email address included at the end of his conversation.

Ms. Merel Nissenberg offers the National Alliance of State Prostate Cancer Coalition’s stance on hypofractionated radiation therapy.

Finally, Ron B. tells us about his experiences with stereotactic body radiation therapy. He has some advice for those of you in a similar situation to the one in which he found himself.

We suggest you read through this month’s conversations and then send the issue to your health care team so that you can discuss the contents with them.

Download the issue.